The cutaneous T-cell lymphomas (Mycosis Fungoides and the Sezary Syndrome) comprise a group of indolent neoplasms of mature T-cell phenotype, the etiology of which is poorly understood. The clinical spectrum of these neoplasms varies from one of chronic skin involvement to one of aggressive disease with organ infiltration and circulating malignant T-cells. Since it has been suggested that early stage skin lesions comprise a polyclonal rather than a monoclonal population, it is unclear whether the disease arises from an event in a T-cell precursor, or whether it arises out of a T-cell response to an event, or possibly a viral infection in an accessory cell. We are attempting to address this question by determining the clonal nature of early stage skin infiltration using PCR amplification and sequencing of T-cell receptor rearrangements in the skin. We are also studying the role of suppressor gene mutation in the evolution of the disease and we have detected p53 mutations in several patients with advanced stage disease. We are exploring the hypothesis that a retrovirus may be implicated in the pathogenesis of this disease by studying patient materials for retroviral-like sequences and by culturing cells from patients and attempting to isolate retroviral activity. In addition, we have studied response to growth factors and cytotoxic activities of a number of pharmacologic agents in MF cells and in Hut 78, an MF cell line, in an attempt to derive new therapies for patients.